The safe will open automatically (it's behind a picture on a wall in the Master bedroom) if you've found/examined everything important up to that point. (Watson will be standing in front of the safe and will shout out, so you'll hear him even if you're not in the room at the time.)

If that hasn't happened, you've missed something -- probably a footprint or a small blood stain. For footprints, crouch and be sure you have the eye icon and click so that Holmes comments. Similarly for blood stains; always click to let the game know that you've seen it.

This part of the game is really picky and there's so much to do before the safe reveals. Hope you find what you've missed. Keep us posted.